Eprenetapopt (APR-246) and Azacitidine in TP53-Mutant Myelodysplastic Syndromes.
Eprenetapopt (APR-246) and Azacitidine in TP53-Mutant Myelodysplastic Syndromes.
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Eprenetapopt（APR-246）和阿扎胞苷治疗TP 53突变型骨髓增生异常综合征
DOI：
10.1200/jco.20.02341
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发表时间：
2021-05-10
期刊：
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通讯作者：
Komrokji RS
中科院分区：
文献类型：
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作者：
Sallman DA;DeZern AE;Garcia-Manero G;Steensma DP;Roboz GJ;Sekeres MA;Cluzeau T;Sweet KL;McLemore A;McGraw KL;Puskas J;Zhang L;Yao J;Mo Q;Nardelli L;Al Ali NH;Padron E;Korbel G;Attar EC;Kantarjian HM;Lancet JE;Fenaux P;List AF;Komrokji RS
大约20%的tp53突变骨髓增生异常综合征（MDS）患者使用低甲基化药物可实现完全缓解（CR）。Eprenetapopt （APR-246）是一种新型的、一流的小分子药物，可在p53突变细胞中恢复野生型p53功能。这是一项Ib/II期研究，旨在确定eprenetapopt与阿扎胞苷联合应用于tp53突变MDS或骨髓母细胞率为20%-30%的急性髓性白血病（AML）患者的安全性、推荐II期剂量和疗效（ClinicalTrials.gov标识号：NCT03072043）。55例至少有一种TP53突变的患者（40例MDS， 11例AML和4例MDS/骨髓增生性肿瘤）接受治疗。总体缓解率为71%，44%达到CR。MDS患者中，73% （n = 29）缓解，50% （n = 20）达到CR， 58%（23/40）细胞遗传学缓解。AML患者的总有效率为64% (n = 7)， CR率为36% （n = 4）。新一代测序结果显示，只有TP53突变的患者有更高的CR率（69% vs 25%; P = 0.006）。免疫组化结果显示，应答患者TP53变异等位基因频率和p53表达显著降低，其中21例（38%）患者达到完全分子缓解（变异等位基因频率< 5%）。中位总生存期为10.8个月，有应答的患者比无应答的患者显著改善（14.6个月vs 7.5个月；P = 0.0005）。总体而言，55例患者中有19例（35%）接受了同种异体造血干细胞移植，中位总生存期为14.7个月。不良事件与阿扎胞苷或依prenetapopt单药治疗相似，最常见的≥3级不良事件是发热性中性粒细胞减少（33%）、白细胞减少（29%）和中性粒细胞减少（29%）。依普那他普和阿扎胞苷联合治疗对tp53突变MDS和少母细胞性AML患者具有良好的耐受性，临床反应率高，分子缓解率高。
Approximately 20% of patients with TP53-mutant myelodysplastic syndromes (MDS) achieve complete remission (CR) with hypomethylating agents. Eprenetapopt (APR-246) is a novel, first-in-class, small molecule that restores wild-type p53 functions in TP53-mutant cells. This was a phase Ib/II study to determine the safety, recommended phase II dose, and efficacy of eprenetapopt administered in combination with azacitidine in patients with TP53-mutant MDS or acute myeloid leukemia (AML) with 20%-30% marrow blasts (ClinicalTrials.gov identifier: NCT03072043). Fifty-five patients (40 MDS, 11 AML, and four MDS/myeloproliferative neoplasms) with at least one TP53 mutation were treated. The overall response rate was 71% with 44% achieving CR. Of patients with MDS, 73% (n = 29) responded with 50% (n = 20) achieving CR and 58% (23/40) a cytogenetic response. The overall response rate and CR rate for patients with AML was 64% (n = 7) and 36% (n = 4), respectively. Patients with only TP53 mutations by next-generation sequencing had higher rates of CR (69% v 25%; P = .006). Responding patients had significant reductions in TP53 variant allele frequency and p53 expression by immunohistochemistry, with 21 (38%) achieving complete molecular remission (variant allele frequency < 5%). Median overall survival was 10.8 months with significant improvement in responding versus nonresponding patients by landmark analysis (14.6 v 7.5 months; P = .0005). Overall, 19/55 (35%) patients underwent allogeneic hematopoietic stem-cell transplant, with a median overall survival of 14.7 months. Adverse events were similar to those reported for azacitidine or eprenetapopt monotherapy, with the most common grade ≥ 3 adverse events being febrile neutropenia (33%), leukopenia (29%), and neutropenia (29%). Combination treatment with eprenetapopt and azacitidine is well-tolerated yielding high rates of clinical response and molecular remissions in patients with TP53-mutant MDS and oligoblastic AML.